12 February 2024

Obesity may not wreck the body’s defense system against weight gain


When people overeat for a period, their brain helps to reduce their appetite to compensate afterwards. This natural defense against weight gain might be less effective in people with obesity. But scientists at the University of Copenhagen were surprised to find that mice with obesity still demonstrated this defense mechanism.

Person saying no to donuts and soft drink

A person’s body weight arises from a complex interplay between their genetics and environment. Rapid changes to our modern environment, affecting everything from the food we eat, the chemicals we are exposed to, our lifestyles and sleep, all contribute to the increasing prevalence of obesity. But even in the most obesity promoting environments, a substantial number of people remain slim, which suggests that they harbor a biological protection against weight gain.

Some scientists believe that obesity disrupts the body's ability to regulate weight through various physiological and molecular changes. This produces a vicious cycle, as weight gain reinforces itself as the biological defenses against weight gained are weakened. However, the relationship between obesity and the strength of these defense systems is poorly understood.

Surprising discovery

To shed new light on the topic, scientists from the University of Copenhagen studied mice, who also possess the same biological defenses against weight gain as humans. Lean and obese mice were overfed, then allowed to eat normally, in order to see whether there were any changes to their feeding behavior and weight recovery. The scientists were surprised to find that the obese mice – who weighed twice as much as the lean mice – naturally reduced their food intake and lowered their body weight after overfeeding, as the lean mice.

“It is widely believed that obesity creates irreversible effects that damage the body's ability to regulate appetite and energy balance. Therefore, it was surprising for us to discover that very obese mice are just as good as lean mice at regulating their weight down in response to overfeeding,” says Camilla Lund, a former PhD Student from the NNF Center for Basic Metabolic Research (CBMR) at the University of Copenhagen. She and CBMR Postdoc Pablo Ranea-Robles were first author on the research that was published in Nature Communications.

Potential to support new therapies

The scientists also tried to understand what was going on biologically to explain these results. It’s well understood that the brain plays an important role in regulating appetite. They discovered that two known molecular mechanisms for regulating appetite were not responsible for biological defense of weight in mice. They also discovered that the levels of the molecule legumain were increased in the blood of overfed mice, and therefore could play a role in weight defense.

“This fascinating work that Camilla and Pablo started is just the first step of an ambitious journey to map all molecules involved in defending against weight gain. The implications of this research are profound. Understanding the body's inherent defense mechanisms against weight gain opens avenues for designing effective weight gain prevention strategies and for developing safe treatments for obesity,” says senior author Associate Professor Christoffer Clemmensen, from the NNF Center for Basic Metabolic Research at the University of Copenhagen.

Read the paper in Nature Communications: ‘Protection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R’